Many people have cancer, most people do not know what cancer is but know instinctively that it is bad. Cancer has trailed humanity since the beginning of our creation and will most likely exist in the end. Cancer acts like a silent killer, waiting patiently until it is the right moment to strike. How cancer remains so hidden is that the cells that are cancer multiply uncontrollably, this causes many mistakes in the DNA of the cells creating different strands of DNA meaning that the cancer itself changes becoming more immune or weaker to different kinds of the body's attacks. This is what makes cancer so powerful, its ability to change so rapidly that the body can’t keep ending up losing its resources. This is how cancer kills so many people every single day. 

But by using this method to enhance our own immune system cells to adapt, we will be able to hunt down cancer cells much more efficiently and be able to help millions of people. This technology may also be able to be used for other diseases that trick your immune system. Disesases such as rabies trick your Killer T Cells and neural cells to make them attack your own organs. By using this technology we can create an artificial immunotherapy technique and teach your immune system to not do things that would eventually lead to multiorgan failure. 

 

Method-

Many methods are used to eradicate cancer but with no certainty, when it comes to cancer there is never a guarantee. Only good and bad chances, this method of cancer eradication gives a higher chance of survival and short recovery times. This chosen method uses OI meaning organoid intelligence, this is a new technology that is being researched in laboratories around the world. OI is intelligence that can be influenced by genetic modifications and is usually in the forms of neural pathways or neurons. But what my project also introduces is a possible way to rapidly regrow cells and possibly limbs.An experiment done in a laboratory in Australia at Cortical labs tested OI’s capabilities and what it can do on a low level. The experiment included brain cells that were modified and trained to be able to play a game of pong. 

 

Human brain cells in a dish learn to play Pong

 

In this game actual brain cells play an old game of pong, an old arcade game. In this game the movements of the slider controlled by the cells is very slow and can look like it is undecided on whether to move or not. You might be thinking what is so special about these brain cells and what they can do that AI cannot. The advantage is in the cells themselves, as we learn the brain creates millions of neural connections every day. It then strengthens the more consistently used pathways and deactivates the new ones. This is how we grow and become better at things, that is what is happening in the petri dish of brain cells. They are getting better and learning rapidly, much faster than any AI would be able to do. Although AI may start with a better skill set they won’t learn much at all. 

 

Research 

This is what I find fascinating about this experiment, our own experiences cultivate and grow parts of our own brain. This is what makes every single individual different from everyone else, creating uniqueness. Studies show that computers exceed humans in simple things such as arithmetic but human minds excel at complex problems. This is because the human mind is able to process information at an extreme rate of speed, much faster than any supercomputer. The chart down below shows a comparison between the Frontier supercomputer (As of 2024 November the fastest supercomputer) and a human brain. Some of the measurements of the brain are estimated as we can’t yet create an exact measurement. 

The speed of the supercomputer allegedly surpasses that of a human, the computer uses about the same amount of energy as a human brain. The cost of the supercomputer is $600 million dollars whereas the human mind is not applicable. The supercomputer uses 145 km of cables whereas the human mind uses of a whopping 850 000 km of axons (the long cable that comes out of the neuron to interact with other cells) and dendrites ( basically a tree branch like pattern that is at the ends of the actual cells, it helps to receive input from other neurons and cells). The human mind has an incredibly large storage amount of information and memory. A human mind has about 2.5 petabytes of memory while the Frontier supercomputer has 75 TB/s. One petabyte is exactly 1000 terabytes and one terabyte is 0.001 of a petabyte. This shows 

This shows that the human mind is much more superior than a machine. My project's goal is to establish a connection between the mind and immune cells to fight respiratory cancer and possibly speed up the healing process.

    

      

 

 

 

 

How is Organoid intelligence grown and developed? 

Organoids are small 3D versions of tissue mimicking and replicating the functions of real tissue. The real development of artificial organoid intelligence is an extreme breakthrough in science opening a whole new world of exploration and discovery. Scientists think that by applying OI to our computers could potentially improve the speed, computational efficiency and data memory. A perfect example of OI in perfection is that it would be able to send biofeedback, this can create extraordinary machine learning capabilities. All of these figures show the complications of OI and its maintenance. But applying this to Immune cells will be equally difficult. I am showing this information to show an example of how a type of OI is developed and grown. 

 

The actual development of OI is very complex and extraordinary, many attempts have been made to replicate the human mind. This has been beyond difficult, although there have been successful attempts to replicate animal brains, but all the ones that have been done to replicate human minds have failed. All of these solutions solve a problem that have come up in tested experiments. Please keep in mind that all of these experiments and pictures were taken off of (not copied) : 

https://www.frontiersin.org/journals/science/articles/10.3389/fsci.2023.1017235/full

 

Figure 1 - 

In the first solution to create OI the center of the cell would be the brain cell culture (cells removed from a biotic being or cells that are artificially grown in a favourable environment). The cell will do the computations, to optimize learning potential the environments will be enriched by cells and genes which is essential for learning. The strength, durability and viability will be supported by microfluidic systems. Different types of input such as electrical and chemical signals, synthetic signals which replicate natural signals from a machine and connected sensory organs. What is expected as output is high resolution measurements by electrophysiological recording seen via specialized 2D or 3D MEA (microelectrode array which can be used to record everything all at once by using several sites for stimulation and extracellular recording). Or from implantable probes that measure the electrophysiological readings as well as the                         imaging of the organoid structure and the functions. The expected output could immediately be used for direct computational purposes and biofeedback to promote organoid learning and understanding. AI will be used to decode and encode signals created by the organoid. 

 

 

Figure 2 - 

Figure 2 advances much further into 3D cell culturing providing many possibilities to explore organoid intelligence. Neural cell cultures have essential advantages for biological learning compared to simple 2D monolayers. This project has a far greater cell density, enhanced synaptogenesis (which is improved functions in the part of the neuron that sends chemical messages to different cells), high levels of myelination (the sheath that protects and covers the   axon a long string that holds the synapses), as well as cell enrichment which will be essential for self learning. The brain organoid will differentiate over time usually 4 to 15 weeks showing neurons and astrocytes (astrocytes are a glial cell that help protect and repair the central nervous system). Over the 4-15 weeks a protein called MAP2 ( microtubule associated protein 2, which is an oligodendrocyte which means that it creates myelin sheaths to cover the axon) will produce the myelin sheaths to cover the axon. Images taken using a microscope with 20x with 63x magnification shows that MAP2 appears as early as 4 weeks with glial cells (cells that support the central nervous system) appearing at 8 weeks. The number of cells will increase over a few weeks.     

 

These features show different advantages that can improve biocomputing, a potential in biocomputing. An attribute to this theory is because the cell density in the 3D models is incredibly similar to in vivo (In an  organism) than in regular monolayer cultures.   Secondly these samples showed much higher   electrophysiological and reactivity to electrical   stimulation. This ensures the presence of active synapses ( the part of a neuron that allows it to   communicate with one another). Comparing this sample on an electroencephalogram (a test that   measures your brain's electrical activity) or EEC shows that this sample is similar to a human   preterm baby. The third reason is that the axons in these organoids show excessive myelination.   Only about 40% of the axons were myelinated   which is about 50% of the human brain. Myelin   reduces capacity of the axonal membrane and   enables saltatory conduction (the method that   nerves use to create impulses to move down a   myelinated axon). This happens at the nodes of Ranvier. Myelination increases electrical   conductivity by approximately 100 fold. The last reason is that these organoid cultures are able   to be enriched with multiple cell types that are   able to cells such as oligodendrocytes, microglia and astrocytes (all of these cells exist for the care of the immune system). Glial cells which help keep the nerve cells in place are especially important to ensure that the synapses stay pruned. IEGs (Immediate early genes ) are expected to boost the learning capacities and memory of these organoids. This experiment wanted to extend this experiment creating organoids with about 10 million neural cells.

 

 

 

 

 

 

 

 

Figure 3 -  

3D microfluidic devices will support scalability as well as long term homeostasis which is a balanced state in which is needed to survive and function properly. Cells in brain organoids require oxygen to combust adenosine triphosphate (ATP), nutrients and growth factors (cytokines that stimulate cell growth and development). It also requires the movement of waste such as CO2 and other products. Passive diffusion (when a solute goes to an area of lower concentration) penetrates to a depth 300 micrometers. This allows necrosis to occur and the larger organoids will give in to starvation.This prevents the organoid from being scaled up to the size required for research and durability. 3D microfluidic devices enable greater scalability and durability by giving controlled perfusion (passage of bodily fluids) throughout larger organoids. 3D spatiotemporal (drug delivery) dosing of chemicals for signaling purposes.

Microfluidic systems substitute vascular systems allowing oxygen and nutrients to come in and allowing waste products such as carbon dioxide to exit. This is crucial for scalability and growth, this is also essential for the durability of the brain organoids. This will support homeostasis and viability for an in vivo like model. Self-folding microfluidics can already deliver chemicals with 3D spatiotemporal control. Recent advances in 3D printing allows us to use perfusable scaffolds                                              

Scaffolds are usually made of polymeric biomaterials (synthetic or natural materials used for interfacing in biological systems to regenerate and or augment and repair tissue) to provide a structure for attaching cells and tissue development.The microfluidic systems will also support chemical signaling ro organoids. Using this we can send growth factors to improve scalability, the importance of spatiotemporal chemical patterns is very well established in neuroscience. 3D spatiotemporal microfluidic interfaces can now enable localized dosing and replication of  chemical environments with neurotransmitters (a signaling molecule made by a neuron to affect another cell across a synapse), neuropeptides (substances produced and released by neurons that act on neural substrates, a neural substrate is a part of the central nervous system). As well as neurochemicals which play a role in neural activity. 

 

3D microelectrode arrays for brain organoids -

Reproducible systems to record electrophysiological output from the brain organoids is essential for developing the OI systems and will need to address challenges in reading and writing to create complex neural assemblies (neurons that participate in collective activities). Brain machine interface technologies have been in progress for at the very least two decades but remain primitive. MEAs or microelectrode arrays form the core of various interfaces because they can be used to stimulate and or record. However most MEAs are in a 2D chip based structure. Intentionally designed for use in monolayer cell cultures. This represents a very likely problem with brain organoids being 3D spherical structures. This makes limited contact with this 2D MEA chip. Another reason is that 2D electrode chip interfaces are rigid and a small mismatch in the stiffness of the recording interface and cell system compromises performance. 

Therefore others develop 3D MEA chip interfaces that are specifically designed for Organoid intelligence. EEG caps will be put on a human which are used to test electrical brain activity on the scalp. The organoids are grown in a soft flexible coating which will be covered in a nanostructure with probes to measure brain activity. The presented model allows us to create a multichannel simulation and record spatiotemporally (referring to recording something in different locations using sensors over a period of time) across the entire surface of the organoid with the multiple channels being able to read multiple areas of the organoid. With excellent resolution,with enhanced recording surface areas. THe response to chemical stimuli using neurotransmitter gradients such as GABA (glutamate aminobutyric acid), dopamine, serotonin and acetylcholine can be recorded to address and change synaptic plasticity. 

 

Figure 4 - 

Intertwining the MEA’s (microelectrode arrays) will allow us to both stimulate and or record electrophysiological output. Organoid interfaces with MEA’s replicated and were inspired by the Electroencephalogram (EEG). To replicate this the organoid will be grown in a flexible soft shell multielectrode nanostructure with probes. The interfaces will give a high resolution 3D spatiotemporal recording of the Organoid.  The microfluidic systems can be combined or integrated into the MEA cover. This will increase and support scalability and durability of the organoid. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

High-resolution implantable electrophysiological devices - 

The MEA shells will give a high resolution 3D electrophysiological recording with very little disruption. But future systems will allow the organoids to grow around the implantable electrodes. This will greatly enhance the signal resolution and the electrophysiological recordings. Although this may be efficient you also have to take into account the invasiveness and possible negative side effects. They could also cause irreversible damage to the organoids. Neuropixels are new technology and are silicon probes that were specialized and developed for cellular recording in vivo which were mostly mice and rats. They can be directly integrated into the organoid. Or it can be integrated into the shells. These small implantable neural devices can read hundreds of neurons electrical signals with little error. They can also be combined with different things such as playing a part in electrical stimulation as well as being able to increase the scale of the input and output

 

They can also be used to map out the Organoid using electrical signals. Neuropixels are also durable and lasted in mice and rats at a consistent rate of 150 days or longer with minimal damage. However the most difficult part of applying the neuropixels is the application itself. The minimum size of the probe must be at least 1 x 4 millimeters to allow space for the microfluidic devices. Because the organoid will be growing the probe or neuropixel will have to be exchanged regularly for the overall health of the organoid. A microfluidic chamber that accounts for the growth will be needed. This chamber will act like a skull and a type of hydrogel will replicate the role of cerebrospinal fluid. When the organoid is more developed a membrane interface will be needed to be able to penetrate the cell membrane while the organoid is in an aqueous surrounding. The Neuropixel will need four shanks (the part of a tool in between the operational area and the handle) for stability in the aqueous environment. A Neuropixel that is 1 mm deep can detect and read %14 of the cells. The probe itself would displace or move approximately %1.5 of the cell, this experiment on neuropixels was done on rats and mice.    

 

Respiratory Cancer and how do we get it?

Respiratory cancer is like many cancers but can cause a lot more damage to your respiratory systems. But to answer that we first have to answer why we get cancer. Cancer occurs when any type of cell begins to mutate because of gene damage. Gene damage can occur from things such as radiation etcetera. But the major cause of respiratory cancer is smoking, smoking causes 80% of all respiratory cancer will be shown below:

 

12, 24, and 60 months were 42.4%, 65.2%, and  82.6%. This shows that there are not very high chances of survival in respiratory cancer caused by smoking. What causes cancer when you smoke, is the poisons in tobacco smoke harm and change the genes in the cells. This happens when specific genes in the same cell mutate within a chromosome, these specific genes are called oncogenes. If they are not fixed it can turn into cancer, but that is why our bodies have proto-oncogenes. Proto-oncogenes contain proteins that help fix and repair our genes and prevent corruption of the cells. But the more times that our cells multiply the more likely that something is going to go wrong. But the potency and amount of proto-oncogenes also decreases with age, that is why elderly people are more likely to have cancer rather than a teenager.

  

 

How Organoid Intelligence will create Immune Cells to find Respiratory Cancer -

In order to create our own cells it will take too much work because we would then have to make our own organs which is incredibly time consuming and expensive. We would also experience possible blood and cell rejection which could result in serious injury and or death. So instead of basically making our own body and organs, instead we will use the recipient's body ro make our own immune cells. That way there is no major risk of blood and or cell rejection, so that by using the organoid we can transmit our own electrical signals. To areas such as the bone marrow to create neutrophils (important immune cells). But we can communicate with our immune system through our own neuroendocrine system and release neurotransmitters like epinephrine, norepinephrine and acetylcholine. But studies show that our own immune cells can also release neurotransmitters and produce them. The neurotransmitters flow through the vascular systems activating or sending messages to whomever the transmitter is received by. 

 

This shows that the brain and nervous system have a deep and profound connection to the immune system that has evolved over millions of years. By exploiting this connection between the nervous system and the brain we will be able to make our own specialized cells or make more cells that destroy respiratory cancer. The immune system has been evolving for millions of years but to things such as cancer it becomes more difficult because enemies like that evolve too. But cancer is in everyone, you’ve had it and killed it probably a few minutes ago. That shows how often we get cancer which is basically abnormal cell growth, it is usually killed by immune cells such as natural killer cells and killer T cells. But the thing is that if the cancer mutates fast enough before its found then it will be able to hide, metastasis (spread cancer via bloodstream or lymph system). This is when cancer starts to become dangerous. But when you steal resources from the body you don’t really want to be found, that’s why our body created MHC class 2 windows. They are basically the windows in a shop that show what that store produces, what the MHC class 2 windows do is show what the cell has been making to show it hasn’t been infected by bacteria. To hide itself the cancer may make less windows, This is when NK cells (natural killer cells) and Killer T cells start to become suspicious and kill the cell along with the cancer. 

 

The Immune System  

You may have heard of something called an immune system, it is the very thing that keeps us all alive but most of us don’t even know what it is. The immune system is an intricate network of cells that fight for us everyday against bacteria, viruses, pathogens, amoeba etc. But there are two systems in the immune system, first is the innate system that is passive and always active to protect your body against daily enemies like bacteria. The innate immune system has cells such as macrophages, dendritic cells and neutrophils. The other system is the Adaptive system which is only activated when there are more foreign pathogens and are harder to fight. This side of the adaptive immune system has cells such as B lymphocytes or B cells that are like tanks shooting antibodies at enemies, as well as T lymphocytes or T cells that assist in the activation of the Adaptive immune system and motivate and re-energize other cells. There is a vast collection of cells that I can’t say in this paragraph but in the short term the immune system is like an infinite library with different cells that are designed to fight different things. 

 

 

 

N/A

Conclusion

By using the organoid to take advantage of it's electrical signal capabilities we can connect the organoid to the body using cooner wire. A wire that is very similar to that of an axon of a neutron, essential to be able to send signals properly. By training the organoid by using microelectrode array's (MEA's) to send signals to the body saying to create more cells, we can use the thymus and femur (the top immune cell producing organs in the body). To create more cells, more speciffically Natural Killler Cells and Killer T Cells, the top cancer hunters in the body. To help us fine the organoid, the more cells the more likely that we can find the cancer. Using Positron Emission Tomography (PET) scans which injects a radioactive tracer that emits positrons, that interacts with the electrons inside the body. That produces gamma rays that can be detected by the scanner, or a Magnetic Resonance Imaging machine (MRI) which tracks bodily fluids and organs. By using these scan methods we can see where the cells commonly converge, we can then assume that possible cancer cells will be there. But this can be taken a step further, in the unlikely event that we find the cancer before the body does, we can injrct cytokines and proteases directly to the area of the cancer. Automatically signaling to the body taht the cancer is there, and the body canc start on attacking the organoid.

https://www.frontiersin.org/journals/science/articles/10.3389/fsci.2023.1017235/full

Neuroimmune Interactions: From the Brain to the Immune ...

National Institutes of Health (NIH) (.gov)

https://pmc.ncbi.nlm.nih.gov › articles › PMC5866360

https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2024.1339317/full 

 

Impact of smoking on mortality of patients with non-small cell lung cancer - PMC 

 

https://www.cdc.gov/tobacco/campaign/tips/diseases/cancer.html#:~:text=Poisons%20in%20tobacco%20smoke%20can,and%20create%20a%20cancer%20tumor.  

 

https://www.youtube.com/watch?v=1AElONvi9WQ 

https://www.youtube.com/watch?v=uoJwt9l-XhQ

Acknowledgements

These are all of the people that helped support and inspire me throughout this project and whom I am very grateful for. Some of them were even the actual reason I even began this project in the first place. 

My Grandpa                                                                     My Mom                                                                                                                                                   

My Dad                                                                       Mrs. Strohbach

Mr. Hagen